Oral compositions for calculus retardation



United States Patent Office 3,535,420 ORAL COMPOSITIONS FOR CALCULUS RETARDATION Homer W. McCune, Wyoming, and Nathaniel B. Tucker, Glendale, Ohio, assignors to The Procter & Gamble Company, Cincinnati, Ohio, a corporation of Ohio No Drawing. Filed Dec. 11, 1967, Ser. No. 689,265 Int. Cl. A61k 7/16 US. Cl. 424-49 Claims ABSTRACT OF THE DISCLOSURE Oral compositions, such as toothpaste, mouthwash, and the like, containing a cyclic tetraphosph'onic acid or salts thereof which retard dental calculus formation Without damaging tooth structure.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is related to the application of Homer W. McCune and Nathaniel B. Tucker, Ser. No. 444,030, filed Mar. 30, 1965.

BACKGROUND OF THE INVENTION The field of this invention is oral compositions which term is used herein to designate products which are not intentionally ingested in the ordinary course of usage but are retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces. Such products include, for example, dentifrices, mouthwashes, topical solutions and prophylaxis pastes.

Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of the teeth at the gingival margin. Supragingival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and second molars, and on the distal surfaces of the posterior molars.

Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxylapatite crystal lattice srtucture similar to bone, enamel and dentine. An organic portion is also present and may consist of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various types of microorganisms.

As the mature calculus develops, it becomes visibly White or yellowish in color unless stained or discolored by some extraneous agency. In addition to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are a contributing factor to gingivitis and other diseases of the supporting structure of the teeth, the irritation caused by deposits of calculus decreasing the resistance of tissues to endogenous and exogenous organisms.

A wide variety 'of chemical and biological agents have been suggested in the art to retard calculus formation or to remove calculus after it is formed. Mechanical removal of this material periodically by the dentist is, of course, routine dental office procedure.

The chemical approach to calculus inhibition generally involves chelation of calcium ion which prevents the calculus from forming and/ or breaks down mature calculus by removing calcium. A number of chelating agents have been employed for this purpose. See, for example, British Pat. 490,384, granted Feb. 15, 1937, which discloses oral compositions containing ethylenediaminetetraaectic acid, and related polycarboxylio acids as anticalculus agents; German Auslegeschrift 1,149,138, published May 22, 1963, which discloses certain water-soluble diglycolates as anticalculus agents; and U.S. Pat. 1,516,206 which discloses 3,535,420 Patented Oct. 20, 1970 oral compositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelators are purportedly safe for use on dental enamel, the chemical similarity of calculus to the tooth structure limits the usefulness of the chelation approach since the more effective chelators can seriously damage the tooth structure by decalcification. Thus, the development of oral compositions which effectively retard calculus by calcium chelation has been impeded by safety considerations. Safe and effective anticalculus have been developed (e.g., U.S. Appln. Ser. No. 668,702, filed Sept. 18, 1967, by Homer W. McCune and Nathaniel B. Tucker), however, researchers continue to seek alternative anticalculus agents for use in oral compositions.

SUMMARY OF THE INVENTION It has now been discovered that a cyclic tetraphosphonic acid having the composition C H O P and the structural formala:

and pharmaceutically acceptable salts thereof (referred to collectively hereinafter as cyclic tetraphosphonates) possess the surprising capacity to retard the development of dental calculus without removing calcium from dental enamel or otherwise damaging the tooth structure when employed in oral compositions maintained within defined pH limits.

Although the cyclic tetraphosph'onates are calcium sequestrants, they retard calculus formation by a mechanism that is believed to involve the inhibition of hydroxylapatite crystal growth rather than calcium sequestering as will be discussed more fully hereinafter.

Unlike inorganic polyphosphates such as pyrophosphates, the cyclic tetraphosphonates employed in the compositions of this invention hydrolyze in aqueous products to yield stable and active species and therefore the compositions remain in an active form throughout the normal shelf-life of such products.

It is therefore an object of this invention toprovide novel oral compositions which retard the formation of calculus without otherwise affecting the tooth structure.

It is another object of this invention to provide an improved method for retarding the developing of dental calculus.

Other objects will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION The invention is an oral composition effective in inhibiting the formation of dental calculus without adversely affecting the tooth structure comprising from about 0.01% to about 10% by weight of an anticalculus agent selected from the group consisting of a cyclic tetraphosphonic acid having the structural formula:

and the pharmaceutically acceptable salts thereof, the pH of the composition being within the range from about 5.0 to about 11.0.

Among the pharmaceutically acceptable salts of the cyclic tetraphosphonic acid described above are the alkali J metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), heavy metal salts (e.g., stannous and indium), ammonium salts and low molecular weight substituted ammonium salts (e.g., mono-, diand triethanolammonium).

Mixtures of the acids and salts serve the purposes of this invention.

The cyclic tetraphosphonates can be prepared by any suitable method, however, an especially preferred method is disclosed in copending application Ser. No. 444,030, filed by Oscar T. Quimby, Mar. 30, 1965.

The concentration of cyclic tetraphosphonates in the oral compositions of this invention can range from about .01% to about by Weight. Oral compositions which in the ordinary course of usage may be accidentally ingested in substantial volumes should contain lower concentrations of cyclic tetraphosphonate. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of cyclic tetraphosphonate.

Dentifrice compositions, prophylaxis pastes and topical solutions, the latter two to be administered professionally, can contain up to about 10% by weight, preferably from about 0.1% to about 5.0% by weight of cyclic tetraphosphonate.

The pH of the composition of this invention can range from about 5.0 to about 11. Below about pH 5.0 damage to the dental enamel can occur in spite of the relative safety of the cyclic tetraphosphonates. Above about pH 11.0 difiiculty is encountered in formulating products having satisfactory flavor, mildness and safety. A preferred pH range is from about 6.5 to about 10. The pH of the composition, of course, is determinative of the predominant salt form of the cyclic tetraphosphonate present therein.

While it is not intended that this invention be limited by a particular theory of operation, it has been observed that the cyclic tetraphosphonates encompassed herein interfere with the progress of calculus formation by interfering with the conversion of amorphous calcium phosphate to crystalline calcium hydroxylapatite. Amounts of cyclic tetraphosphonates which are much too small to chelate any appreciable quantities of calcium have been found to retard the formation of calcium hydroxylapatite. This selective action on the formative calculus deposits without demineralizing action on the dental enamel is surprising.

The efficacy of the composition of this invention in calculus prophylaxis was demonstrated by the Rat Calculus and Crystal Growth Inhibition tests which were conducted as follows:

Crystal growth inhibition determination As hereinbefore stated, the polyphosphonates inhibit the growth of calcium hydroxylapatite crystals and in this way interfere with the normal formation of calcium I hydroxylapatite from solution. The Crystal Growth Inhibition Test is to determine the effect of the cyclic tetraphosphonates on the calcium phosphate formed on addition of calcium ion to orthophosphate ion at constant pH. The procedure is as follows:

1 ml. of a 0.1 M stock solution of NaH PO -H O is diluted with 22 ml. of distilled water. 1 ml. of an aqueous solution of the hexasodium cyclic tetraphosphonate at a concentration sufiicient to provide the desired ultimate concentration in the reaction mixture is added to the diluted NaH PO solution and the solution is adjusted to pH 7.4 with sodium hydroxide. To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodium hydroxide. This mixture is held at a constant pH 7.4 throughout the reaction period.

After a sufficient reaction time as determined by the operator, generally within 90 minutes, the solution is filtered through a 0.45u Millipore filter pad, dried, and analyzed by X-ray diffraction. The solid calcium phos- 4 phate precipitated from the above-described solution without a cyclic tetraphosphonate gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the same conditions but in the presence of small amounts of the cyclic tetraphosphonates of this invention is amorphous to X-rays.

Those compounds which are effective in inhibiting the growth of hydroxylapatite crystals at concentrations of less than 1.5 10 M under the conditions of this test are also effective in reducing calculus formation in rats, while several compounds outside the scope of this invention that have little or no effect in this test did not reduce calculus in rats.

When tested in the Crystal Growth Inhibition Test, the hexasodium salt of cyclic tetraphosphonic acid was found to inhibit crystal growth at a concentration of 1.99 10 M.

Thus, the presence of 1.99 10 M of the hexasodium salt of cyclic tetraphosphonic acid in the test solutions of the Crystal Inhibition Test results in the precipitation of an amorphous calcium phosphate rather than crystalline calcium hydroxylapatite as occurs without polyphosphonate. By way of comparison, ethylenediaminetetraacetic acid and nitrilotriacetic acid which have been suggested for use as anticalculus agents in the art fail to inhibit hydroxylapatite crystal growth at molar concentrations of 2.45 l0 and 2.54 10- respectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their removal of calcium ion from solution by their sequestering properties, not by their crystal inhibition properties.

The safety of polyphosphonates for use in contact with dental surfaces is determined by the Continuous Immersion Test conducted as follows: Mature human teeth are immersed in aqueous solutions or dispersions of oral compositions containing a cyclic tetraphosphonate in accordance with this invention at pH 7.0 and pH 10. Every four hours the teeth are examined for decalcification. Under visible light, enamel decalcification can be detected by a loss of luster, white opaque sports or slight surface roughening. The teeth are examined macroscopically and microscopically at the end of seven days. If no decalcification is observed through this period, the compositions cause no damage to dental enamel, and are considered safe in this respect for use in the oral cavity.

A detifrice, especially toothpaste, containing a cyclic tetraphosphonate is a preferred embodiment of this invention. Toothpaste compositions conventionally contain abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents.

The abrasive materials and other adjuncts used in the practice of this invention are preferably not sources of much soluble calcium so that the crystal growth inhibiting capacity of the cyclic tetraphosphonate is not depleted to an extent that its anticalculus activity is impaired. Thus, conventional abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used. However, predominantly fl-phase calcium pyrophosphate prepared in accordance with the teachings of Schweizer, U.S. Pat. 3,112,247, granted Nov. 26, 1963, which contains relatively little soluble calcium can be used. An especially preferred class of abrasives for use herein are the particulate thermosetting polymerized resins as described by Cooley et al. in U.S. Pat. 3,070,510, granted Dec. 25, 1962. Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, melamine-urea-formaldehydes, cross-linked epoxdies, and cross-linked polyesters.

Other suitable abrasives include alumina and the insoluble non-calcium metaphosphates such as sodium metaphosphate. Mixtures of abrasives can also be used. In any case, the total amount of abrasive in the dentifrice embodiments of this invention can range from 0.5% to by weight of the dentifrice. Preferably, toothpastes contain from 20% to 60% by weight of abrasive. Abrasive particle size preferably ranges from 2a to 20 Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably non-soap anionic organic synthetic detergents. Examples of such agents are water-soluble salts of alkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate, water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms, such as sodium monoglyceride sulfonates; salts of C -C fatty acid amides of taurine, such as sodium N-methyl-N-palmitoyl tauride; salts of C -C fatty acid esters of isethionic acid; and substantially saturated aliphatic acyl amides of saturated monoaminocarboxylic acids having 2 to 6 carbon atoms and in which the acyl radical contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more sudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of this invention in an amount from 0.5% to by weight of the total compositions.

In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are hydroxyethylcellulose and water-soluble salts of cellulose ethers such as sodium carboxymethylcellulose and sodium carboxymethylhydroxyethylcellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5 to 5.0% by weight of the total composition can be used.

It is also desirable to include some humectant material in a toothpaste to keep it from hardening. Suitable humectants include glycerine, sorbitol, and other edible polyhydric alcohols. The humectant can comprise up to about 36% by weight of the toothpaste composition.

Suitable flavoring agents include oil of Wintergreen, oil of peppermint, oil of Spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate.

Several representative oral compositions illustrating this invention are set forth in the following examples.

EXAMPLE I A toothpaste of the following composition is prepared by conventional methods:

Parts by weight Water 31.58 Sorbitol 6.25 Saccharin 0.12 Calcium pyrophosphate 1 39.00 Glycerine 18.00 Sodium alkyl(coconut) sulfate 0.40

Sodium coconut monoglyceride sulfonate 0.75 Sodium carboxymethyl cellulose 1.15 Magnesium aluminum silicates 0.40 Flavoring 0.85 Hexasodium salt of cyclic tetraphosphonic acid 2 1.50 pH, 5.90

1 Prepared in accordance with U8. Patent 3,112,247 granted November 26, 1963.

2 As \hereinbefore identified.

This composition effectively retards calculus formation on dental enamel and when tested in the Continuous Immersion Test described herein no decalcification is noted after seven days exposure.

Toothpaste compositions substantially identical to the composition of Example I are prepared with the cyclic tetraphosphonic acid as hereinbefore identified; the dimagnesium salt of cyclic tetraphosphonic acid; the diindium salt of cyclic tetraphosphonic acid; the dicalcium salt of cyclic tetraphosphonic acid; and the distannous salt of cyclic tetraphosphonic acid, respectively, rather than the hexasodium salt of cyclic tetraphosphonic acid, adjusting 6 the pH to 5.9. These compositions substantially retard calculus formation and do not decalcify dental enamel.

Several mouthwash compositions are prepared in accordance with this invention as follows:

Example II III IV X Component Parts by weight Glycerine 10. 0 10. 0 10. 0 10. 0 Ethyl alcohol. 16. 5 16. 5 16. 5 l6. 5 Tween .12 .12 .12 .12 Saccharin a 045 045 045 02 Sodium cyclamate 075 075 075 04 Flavor 088 088 08 8 088 Cyclic tetraphosphonate 2 1 0 3 3 0 4 5.0 6 7. 0

e1 Balance pH adjusted to 7. 0 6.5 10.0 10. 0

1 Polyoxyethylene (20 mol% of ethylene oxide) sorbitan monooleate-a nomomc emulsifier supplied by Atlas Powder Company.

2 Tetraammonium salt; of cyclic tetraphosphonic acid.

3 Di(triethanolammonium) salt of cyclic tetraphosphonic acid.

4 'lrlsodium salt of cyclic tetraphosphonic acid.

6 Hexapotassium salt of cyclic tetraphosphonic acid.

When used in the same manner as conventional mouthwash, at least once daily, each of the above compositions materially reduces accumulation of calculus on the surfaces of teeth. No decalcifiication is observed after seven days exposure of dental enamel to these compositions.

EXAMPLE VI A prophylaxis paste for use by the dentist for removal of stains and polishing the teeth after mechanical removal of calculus deposits is formulated as follows:

Parts by weight Navajo pumice 77.10 TiO 4.00 Glycerine 17.75 Hydroxyethylcellulose .22 Saccharin .33

Hexasodium salt of cyclic tetraphosphonic acid 8.0

When applied to the teeth with a prophylactic rubber cup in the conventional manner, this composition helps retard the development of new calculus deposits.

Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amount of polyphosphonate within the range specified herein, to provide an effective means of retarding calculus formation without damaging the tooth structure.

Those components other than cyclic tetraphosphonate which were included in the foregoing examples and various mixture of those components are illustrative of carriers suitable for use in the oral cavity.

In reference to pH adjustments in the foregoing examples, it is to be understood that a base of a cation corresponding to the salt form of the cyclic tetraphosphonic acid employed is used. In each case in which cyclic tetraphosphonate was added in its acid form to the example compositions, the pH was adjusted to the specified value with NaOH. Adjustments in pH to more acid levels when adding the cyclic tetraphosphonate as a salt is accomplished with HCl. It will be obvious to those skilled in the art that pH adjustments can be made with any acid or base suitable for use in the oral cavity.

What is claimed is:

1. An oral composition effective in inhibiting the formation of dental calculus without adversely affecting tooth structure, comprising from about 0.1% to about 5.0% by weight of at least one anticalculus agent selected from the group consisting of a cyclic tetraphosphonic acid having the structural formula:

and the pharmaceutically acceptable salts thereof, and a carrier suitable for use in the oral cavity, the pH of the composition being within the range of about 5.0 to about 11.0.

2. The composition of claim 1 wherein the anticalculus agent is an alkali metal, alkaline earth metal, stannous, indium, ammonium, or low molecular weight substituted ammonium salt of cyclic tetraphosphonic acid as defined in claim 1.

3. The composition of claim 1 wherein the anticalculus agent is the hexasodium salt of cyclic tetraphosphonic acid as defined in claim 1.

4. A toothpaste composition comprising from about 0.1% to about 5.0% by weight of at least one anticalculus agent selected from the group consisting of a cyclic tetraphosphonic acid having the structural formula:

8 and the pharmaceutically acceptable salts thereof, and from about 20% to about 60% by weight of a dentifrice abrasive, the pH of said composition being in the range from about 5.0 to about 11.0.

5. The composition of claim 4 wherein the anticalculus agent is an alkali metal, alkaline earth metal, stannous, indium, ammonium, or low molecular weight substituted ammonium salt of cyclic tetraphosphonic acid as defined in claim 4.

References Cited UNITED STATES PATENTS Grossman, J. Oral Surg., Oral Med., and Oral Path., vol. 7, pp. 484-487, May 1954.

RICHARD L. HUFF, Primary Examiner 

